Abstract
TP53 is the most frequently mutated gene in cancer. The p53 protein activates transcription of genes that promote cell cycle arrest or apoptosis, or regulate cell metabolism, and other processes. Missense mutations in TP53 abolish specific DNA binding of p53 and allow evasion of apoptosis and accelerated tumor progression. Mutant p53 often accumulates at high levels in tumor cells. Pharmacological reactivation of mutant p53 has emerged as a promising strategy for improved cancer therapy. Small molecules that restore wild type activity of mutant p53 have been identified using various approaches. One of these molecules, APR-246, is a prodrug that is converted to the Michael acceptor methylene quinuclidinone (MQ) that binds covalently to cysteines in p53, leading to refolding and restoration of wild type p53 function. MQ also targets the cellular redox balance by inhibiting thioredoxin reductase (TrxR1) and depleting glutathione. This dual mechanism of action may account for the striking synergy between APR-246 and platinum compounds. APR-246 is the only mutant p53-targeting compound in clinical development. A phase I/IIa clinical trial in hematological malignancies and prostate cancer showed good safety profile and clinical effects in some patients. APR-246 is currently tested in a phase Ib/II trial in patients with high-grade serous ovarian cancer.
Highlights
Recent DNA sequencing of 3281 human tumors within The Cancer Genome Atlas (TCGA) has confirmed the high frequency of TP53 mutations in cancer
Transfer of methylene quinuclidinone (MQ)-modified mutant p53 protein into p53 null tumor cells induces expression of p53 target genes and cell death by apoptosis [18]. These results demonstrate that MQ is the active compound and that MQ-modification of mutant p53 per se is sufficient to induce tumor cell death
The targeting of mutant versions of the two structurally related transcription factors p63 and p73 by APR-246 leads to entirely different biological responses that recapitulate the normal functions of each protein. These results argue convincingly that the biological effects of APR-246 are mediated by direct binding to mutant p53 or p63 and refolding the mutant proteins into an active conformation
Summary
Recent DNA sequencing of 3281 human tumors within The Cancer Genome Atlas (TCGA) has confirmed the high frequency of TP53 mutations in cancer. Accumulating data on the effects of PRIMA-1/APR-246 on the cellular redox balance demonstrate that these compounds have a dual mechanism of action that targets two Achille’s heels of tumor cells: mutant p53 and the redox balance (Figure 2). The targeting of these two pathways may allow more efficient elimination of tumor cells and lower the probability of resistance development. In MCF-7 cells (wild type TP53), chemical hypoxia induced by CoCl2 led to accumulation of unfolded wild type p53, as assessed with the monoclonal antibody PAb240, and enhanced sensitivity to PRIMA-1 This is due to MQ binding and refolding of unfolded “mutantlike” wild type p53 into an active conformation. Due to insufficient blood supply, rapidly growing tumors in vivo are often hypoxic, and it is conceivable that this could enhance the therapeutic efficacy of APR-246, both in wild type and mutant TP53-carrying tumors
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